Accumulating evidence has implicated specific infectious agents, including Chlamydia pneumoniae and Porphyromonas gingivalis in the progression of atherosclerosis. However, the mechanisms by which infections contribute to the progression of atherosclerosis and the links among lipids, microbial antigens, and innate immune and inflammatory responses are not well understood. Toll-like receptors (TLR) are pattern recognition receptors that have key roles in detecting microbes and initiating inflammatory responses. Recently, expression of TLRs has been demonstrated,to be markedly augmented in human atherosclerotic lesions. Our studies indicate that TLR2 and TLR4 expression is enhanced in mouse atherosclerotic lesions following oral challenge with P. gingivalis in an apoE model of atherosclerosis. These are first studies with any bacterial pathogen, which have demonstrated a link between innate immune markers and infection-accelerated atherosclerosis in an animal model. In addition, we have demonstrated that TLR2. TLR4. and MyD88 (cvtoplasmic adapter molecule) are required for host cell signaling in response to P. gingivalis and that TLR2 and MvD88 are required for local inflammation associated with P. ginciivalis infection in a murine model. TLR2 and TLR4 expression is also enhanced in endothelial cells and macrophages in response to P. gingivalis infection and following infection, these cells become primed to respond to TLR4-ligands. Recent studies using TLR4 and MyD88 / ApoE mice have shown a substantial reduction in atherosclerosis lesion development compared to wildtype mice fed a high fat diet supporting the direct involvement of the TLR4 and MyD88-dependent signaling pathway in the development of lipid induced atherosclerosis in mice. Furthermore, our initial analysis of newly generated TLR2 / ApoE mice demonstrate that these mice develop less atherosclerotic plaque as compared to ApoE mice. Together these results raise the possibility that enhanced TLR expression and signaling may play a role in infection accelerated inflammation and atherosclerosis. The aims of this study are: 1. To define the role of bacterial induced systemic and aortic inflammation "in the acceleration of atherosclerotic plaque accumulation in ApoE"'" mice orally challenged with P.-gingivalis at the acute phase. 2. To assess the role of TLR-MyD88-dependent signaling in atheromatous plaque development following P. gingivalis oral challenge. 3. To assess the role of the TLR-2 and TLR-4-dependent signaling pathway in atheromatous plaque development following P. gingivalis oral challenge. Improved understanding of the molecular mechanisms driving TLR over expression and signaling and the role of the resulting chronic inflammation during atherosclerosis may provide new targets for therapy.